This application addresses Challenge Area 15 (Translational Science). Specific Challenge Topic 15-MH-109 Prefrontal cortex regulation of higher brain functions and complex behavior. There is growing emphasis on understanding what might produce resilience to the behavioral and neural impact of stress, and coping factors are thought to play a pivotal role. Behavioral control over the stressor is a key aspect of coping, and the presence of control not only blunts the effects of the stressor being controlled (Maier et al., 2006), but also reduces and even eliminates the behavioral and neurochemical changes produced by subsequent stressors, even if the subsequent stressor is not behaviorally controllable (Amat et al.,2006). That is, the experience of controlling a potent acute stressor appears to "immunize" the organism against the effects of later (acute) stress. Importantly, the ventral medial prefrontal cortex (vmPFC) has been shown to mediate both the immediate and proactive protective effects of behavioral control. The presence of control has been shown to activate top-down vmPFC inhibitory control over stress-responsive brainstem and limbic structures, thereby reducing the neurochemical impact of the stressor, as well as the behavioral sequelae of the activation of these structures (Amat et al.,2005). Furthermore, the experience of control over a potent stressor alters the vmPFC in such a way that subsequent stressors that are uncontrollable now activate vmPFC inhibitory control, thereby leading to protection against subsequent stressor exposure (Amat et al., 2006;Baratta et al, 2008). The research that has explored the resilience-inducing properties of control, as well as the role of the vmPFC in stress-resilience, has focused entirely on acute stress exposure. However, it is chronic stress that is most often implicated as an etiological factor in the development of a broad spectrum of psychiatric and somatic disorders. There has been virtually no study of experiential factors and mechanisms that might be important in producing resistance to the behavioral and neurochemical impact of chronic stress, and the present proposal is addressed at these issues. The research determines whether a) an experience with control over an acute stressor will prevent and/or reverse the impact of a chronic social stressor, adult social isolation, and b) the vmPFC is a critical mediator of these protective effects. Chronic stress is an etiological factor in the development of numerous disorders. Not all individuals exposed to chronic stress are severely impacted, and an understanding of factors that make individuals resilient are likely to lead to new treatments. The proposed research will determine whether a) the experience of behavioral control over a potent acute stressor before exposure to a different chronic stressor will prevent, and/or the experience of control after a chronic stressor reverse, the behavioral and neurochemical effects of the chronic stressor, and b) the protection is mediated by activation of the medial prefrontal cortex by control.